Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the United States, with a dismal 5-year survival rate of 5%, with few effective chemotherapeutic options. It is therefore critical to identify the genetic drives of pancreatic cancer in order to improve diagnostic and treatment capabilities. Recent genetic analyses of human pancreatic cancers have identified mutations in genes encoding several epigenetic regulator proteins that organize or modify chromatin (the organizational structure of DNA in the cell). Modification or remodeling of chromatin structure can repress or activate expression of diverse sets of genes, depending on tissue context and developmental stage. Loss or inappropriate activation of these proteins can thus reprogram cellular gene expression, which can lead to uncontrolled cell division and/or metastatic invasion. While members of this group of genes have been shown to regulate the progression of other cancers, such as leukemia, it is currently unknown whether their dysregulation plays an important role in PDAC, the mechanism by which this might occur, and whether their expression can correlate with patient prognosis or drug response. The proposed project aims to address these questions using two complementary approaches. First, genetically engineered mouse models of pancreatic cancer that reversibly mimic mutations in the genes encoding components of the SWI/SNF complex will be developed. Components of this complex are the most frequently mutated epigenetic regulators in pancreatic cancer. These models will then be used to functionally determine whether loss of the SWI/SNF proteins accelerates tumor growth or metastasis. The reversible nature of the inhibition will also allow for determination of whether their restoration can induce tumor regression. The underlying changes in cellular signaling induced by loss of the complex subunits will also be characterized through transcriptional analysis, which can be used to predict the drug responsiveness of the tumors. Such data will inform prognostic and therapeutic evaluations for patients with mutations in these genes. In parallel, a transplant-based mouse model of pancreatic cancer will be employed to screen through all known epigenetic regulator proteins in an unbiased manner in order to identify those that can suppress the formation of PDAC, meaning that their loss can accelerate pancreatic cancer growth. This comprehensive approach will advance our understanding of the role of epigenetic regulation during cancer progression. Furthermore, the tools generated in this project will also have broad utility for studying many other epithelial cancers that demonstrate frequent mutation of epigenetic regulators.